A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
Cyclopentaquinazoline Compounds and Methods of Synthesis
WO 94/11354 describes tricyclic compounds, having a cyclopenta[g]quinazoline core, which are of general formula (I)
wherein R1 is hydrogen, amino, C1-4alkyl, C1-4alkoxy, hydroxy-C1-4alkyl or fluoro-C1-4alkyl;R2 is hydrogen, C1-4alkyl, C3-4alkenyl, C3-4alkynyl, hydroxy-C2-4alkyl, halogeno-C2-4alkyl or cyano-C1-4alkyl;Ar is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl, which may optionally bear one or two substituents selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4alkyl and C1-4alkoxy; andR3 is a group of formula —NHCH(CO2H)-A1-Y1 wherein A1 is C1-6alkylene and Y1 is carboxy, tetrazol-5-yl, N—[C1-4alkylsulfonyl]carbamoyl, N-(phenylsulfonyl)carbamoyl, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl, wherein said N-(phenylsulfonyl)carbamoyl group may optionally bear one or two substituents on the phenyl ring selected from halogeno, nitro, C1-4alkyl and C1-4alkoxy, or Y1 is a group of the formula —CONH—CH(CO2H)-A2-Y2 wherein the α-amino acid carbon atom has the D-configuration, A2 is C1-6alkylene and Y2 is carboxy or tetrazol-5-yl,or R3 is a N-linked naturally-occurring amino acid selected from the group consisting of L-alanine, L-leucine, L-isoleucine, L-valine and L-phenylalanine,or R3 is a group of the formula —NH-A3-Y3 wherein A3 is C1-3alkylene and Y3 is phenyl which may optionally bear one, two or three substituents selected from the group consisting of halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4alkyl and C1-4alkoxy.
In WO 94/11354 the synthesis of compounds of formula I is described and may involve reacting an acid of formula (II), where R4 is hydrogen or a protecting group, or a reactive derivative thereof, with an appropriate amine R3—H.

Preparation of the acids of formula (II) themselves, by standard procedures, is also described, for example by reaction of a compound of formula (III), where Z is a displaceable group, with an amine of formula HNR2—Ar—CO2R5 where R5 is a carboxylic acid protecting group which can be removed after the coupling to produce compound (II).

The displacements on (III) which are exemplified in WO 94/11354 all involve displacement with compounds of formula H2N—Ar—CO2R5 to form intermediates of formula (IV), which are subsequently alkylated on the C6-nitrogen to form compounds of formula (II).

A method of resolving compounds of general formula (II) to obtain the more active (6S)-enantiomers is also revealed in WO 94/11354. This method involves taking racemic acids of formula (II) and condensing them with a chiral amino acid, preferably L-glutamic acid, or (S)-2-aminoadipic acid to form an amide of formula (V) as a 1:1 mixture of diastereoisomers.
Use of an appropriate protease, such as Carboxypeptidase G2 selectively hydrolyzes the 6S-diastereoisomer, allowing for a straightforward separation of 6S-(II) from the 6R-(V).

This method of resolution is lengthy, as the amide has to be made with an ester of the amino acid, which is subsequently hydrolyzed to an acid of formula (V). Moreover, the enzymatic hydrolysis requires large quantities of the enzyme, and may not be technically or economically feasible to scale up to produce commercial quantities of compounds of formula (I).
Further compounds, of general formula (VI) are disclosed in WO 95/30673
wherein R1 is hydrogen, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl or C2-4-fluoroalkyl;wherein R2 is hydrogen, amino, C1-4alkyl, C3-4alkenyl, C2-4hydroxyalkyl, C2-4halogenoalkyl or C1-4cyanoalkyl;Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4alkyl, and C1-4alkoxy; andwherein R3 is a group of the formula:—-A1-Ar2-A2-Y1 in which A1 is a bond between the α-carbon atom of the group CONHCH(CO2H)— and Ar2, or is a C1-2 alkenyl group;Ar2 is phenylene, tetrazoldiyl, thiophenediyl, pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituent on the ring selected from halogeno, nitro, C1-4alkyl, and C1-4alkoxy;A2 is a C1-3alkylene or C2-3alkenylene group; andY1 is carboxy, tetrazol-5-yl, N—(C1-4alkylsulfonyl)carbamoyl,N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4alkyl, and C1-4alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; orY1 is a group of the formula:——CON(R)CH(Y2)Y3 in which R is hydrogen, C1-4alkyl, C3-4alkenyl or C3-4alkynyl;Y2 is carboxy, tetrazol-5-yl, N—(C1-4alkylsulfonyl)carbamoyl, N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents onthe phenyl ring selected from the group consisting of halogeno, nitro, C1-4alkyl and C1-4alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; andY3 is the residue of a naturally occurring amino acid NH2CH(CO2H)Y3; orY3 is a group of the formula:—-A4-CO2Hin which A4 is a C2-6alkylene group other than ethylene;wherein R3 is a group of the formula:—A5-CON(R)CH(Y4)Y5 in which A5 is a C1-6alkylene group and R is as defined aboveY4 is carboxy, tetrazol-5-yl, N—(C1-4alkylsulfonyl)carbamoyl,N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4alkyl and C1-4alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; andY5 is the residue of a naturally occurring amino acid NH2CH(CO2H)Y5 provided that when R is hydrogen and Y4 is carboxy it is not the residue of glutamic acid; orY5 is a group of the formula:—-A4-CO2Hin which A4 is as defined above; orY5 is a group of the formula:—-A6-Ar3-A7-Y6 in which A6 is a bond between the α-carbon atom of the group -A5-CON(R)CH(Y4) and Ar3 or is a C1-2alkylene group;Ar3 is phenylene, tetrazoldiyl, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituents on the ring selected from halogeno, nitro, C1-4alkyl and C1-4alkoxy;A7 is a C1-3alkylene or C2-3alkenylene group; andY6 is carboxy, tetrazol-5-yl, N—(C1-4alkylsulfonyl)carbamoyl,N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; orwherein R3 is a group of the formula:—-A8-X—Ar4 in which A8 is a C1-4alkylene group;X is sulfinyl, sulfonyl or methylene;and Ar4 is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl or, except when X is methylene, tetrazol-5-yl;the compound (VI) optionally being in the form of a pharmaceutically acceptable salt or ester.
Compounds of formula (I) and (VI) are of use as anti-cancer agents.
Particularly useful are compounds such as those disclosed in WO 03/020748, of general formula (VII)
wherein A is OR0′ or NR0′R1′ and R0′ and R1′ are each independently hydrogen, C1-4alkyl, C3-4alkenyl, C3-4 alkynyl, hydroxy-C2-4alkyl, halogeno-C2-4alkyl or cyano-C1-4alkyl, or R0′ and R1′ together with the intermediate N form a five- or six-membered heterocyclic ring;p is an integer in the range 1 to 4;Ar and R2 are as defined above;and wherein R3′ may, for example, be a group of formula: -A5-CON(R)CH(Y4)Y5 in which A5 is a C1-6 alkylene group; R is hydrogen, C1-4alkyl, C3-4 alkenyl or C3-4alkynyl; Y4 is carboxy, tetrazol-5-yl, N—(C1-4alkylsulfonyl)carbamoyl, N-(phenylsulfonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from halogeno, nitro, C1-4alkyl and C1-4alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulfinyl or tetrazol-5-ylsulfonyl; and Y5 is the side chain of a naturally occurring amino acid or a group of the formula: -A4-CO2H in which A4 is as defined above.
In WO 03/020748, the synthesis of compounds of formula (II) is described, starting from 5-aminoindane. For example, compound 1 (N-{N-{4-[N-((6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclo-penta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid; ‘BGC945’) was prepared as shown in Scheme 1, below.

An improved process for the synthesis of the key tricyclic intermediate, compound 2 is described in U.S. Pat. No. 7,250,511, and is shown in Scheme 2.

In general, existing methods for the synthesis of these compounds are long and commonly exhibit a low overall yield. They also contain steps which may not be suitable for commercial scale production.
This is especially true of the propargylation step (step ix in Scheme 1 and step xiii in Scheme 2, which involves a cationic propargyl cobalt carbonyl complex which is both very expensive to make, and has to be both made and used under rigorously anhydrous and anoxic conditions. Furthermore, it requires removal of the cobalt complex in an additional step. The reaction sequence becomes very problematic on scaling to even tens of grams. Thus it is unsuitable for commercial scale work. Additionally, although the disclosures cited above, and the disclosures in U.S. Pat. Nos. 7,297,701 and 7,528,141, all discuss the fact that compound 2 is produced as a racemate, making compound 1a 1:1 mixture of diastereoisomers, and that the 6S-isomer is the desired, more potent isomer, none of them reveal how to produce compound 2 in enantiomerically pure form without the use of additional steps of amide formation and enzymatic hydrolysis.
As discussed previously, the quantities and cost of the enzymes required, in addition to the fact that the resolution adds a minimum of three steps to the sequence (with the additional costs and losses of material that such inefficiency incurs) mean that these applications do not disclose a process which could be used on a production scale.
The present inventors have developed new processes for the synthesis of these compounds. These new synthetic processes will make the overall manufacturing route considerably shorter, and higher yielding, better capable of being run on a larger scale, and considerably less expensive than the current processes.
Furthermore, they reveal a highly feasible and fully scalable strategy for obtaining compound 2, and any desired analogues, in high enantiomeric purity, allowing compound 1 to be made efficiently in the desired 6S diastereoisomeric form in commercially useful amounts.